Of note, immunotherapeutic strategies blocking proinflammatory cytokines or their receptors are only meaningful in the hyperinflammatory stages; as in the early stages of mild lung injury or minimal inflammation, cytokines are largely desirable in fighting against virus infection. These include inhibitors of IL-1, IL-6, IL-18, TNF, CCR5 and GM-CSF or their receptors. However, some phase 2 or 3 results suggest no or little benefits in moderate and severe patients, and large-scale clinical data in COVID-19 are needed (8, 40–44, 54). Interferons (IFNs) have been used for many years to treat infectious disorders, cancers and multiple sclerosis, suggesting their potent antiviral effects for COVID-19. Although recent studies have found early nebulized IFN-α/β/𝜆 administration accelerated high-risk patients’ recovery and reduced mortality, the multinational clinical trials on hospitalized severe cases indicated subcutaneous IFNs injection with or without lopinavir treatment had minor effects on length of hospital stay and mortality (49, 50, 55, 56).

Small molecule inhibitors targeting cytokine-mediated signaling pathway, specifically of Janus kinases (JAKs), have also been well studied for treating COVID-19. For instance, Baricitinib and Tofacitinib were approved for emergency use authorization (EUA) because the clinical symptoms improved when co-treated with remdesivir during SARS-CoV-2 infection. But secondary infection and thromboembolism are the risk of these kinase inhibitors, which is highly dependent on administration time (45, 46). Glucocorticoids, such as dexamethasone, are broad-acting and powerful immunosuppressive and antiphlogistic therapies that can reduce mortality in critical COVID-19 cases (51). However, many clinical studies demonstrated that such efficacies are inevitably accompanied by multiple adverse effects, including viral reactivation, blocking of the host immune responses important for viral clearance, and others (51). In addition, it is indisputable that inflammasomes contribute to the pathogenesis of COVID-19, and trials on the GasderminD-pore inhibitor Disulfiram and the NLRP3 inhibitors Melatonin are ongoing (47, 48).

Monoclonal antibody (mAb) is one of most effective immunotherapeutic strategies for the treatment of serious viral infection; thus, lots of mAbs are identified purposing to inhibit SARS-CoV-2 infection through binding to the spike protein. So far, the FDA has approved EUA for LY-CoV555 and Sotrovimab in pediatric and high-risk patients to prophylaxis and treat COVID-19, as these antibodies can reduce mortality and hospitalization (52, 57). Nevertheless, viral mutations present in variants/variants of concern (VOCs) have begun to gradually weaken the efficacies of many mAbs, and it is likely some will become invalid without upgrading to compensate for SARS-CoV-2 evolution (53). Altogether, immune system dysfunction plays a key role in COVID-19 pathogenesis and immunotherapeutic strategies for SARS-CoV-2 infection are promising, future efforts to discover more effective agents are obviously warranted. Also note that COVID-19 remains a field of rapid progress, thus recommendations on drugs and biomarkers will continue to evolve.

Multiple studies have shown that IL-22 is involved in lung repair, recovery and regeneration during lung infection or injury. From these studies, it is concluded that IL-22 can be protective or proinflammatory, where IL-22/IL-22R axis is important for host protective immunity to both viral infections and bacterial infections. The tissue protective nature of IL-22 via enhancing wound healing and the epithelial barrier through promoting antimicrobial peptides expression, enhancing anti-apoptosis and antiviral effects and alleviating airway inflammation, as well as inhibiting proinflammatory cytokines produced by airway epithelial cells ( Figure 2 ). In contrast, the proinflammatory of IL-22 is evidenced by its ability to promote the expression of chemokines, and inflammatory cytokines such as IL-1β, IL-17, and TNF-α. Whether IL-22 has a protective or proinflammatory effect seems to depend on the related cytokines co-produced by the relevant cells during different stages of the diseases (10, 14).

Transcription factors play crucial roles in controlling the production of IL-22 in lungs (15, 59–61). Interestingly, studies indicate that these transcription factors, such as aryl hydrocarbon receptor (AhR), c-Maf, Batf, and Notch, can sometimes control IL-22 even in the same cells. These transcription factors form complex regulatory networks and regulate the production of IL-22 in context-dependent manners (62–64). As a cytosolic transcription factor, AhR is a harbor that converges several different environmental and cellular signaling to regulate the development of many Th cell lines, including Tr1, Th17 and Treg cells via recognizing multiple natural molecules and small xenobiotics (62–65). AhR directly binds to cMaf and synergistically enhances IL-22 production in ILC3s, Th17 cells, γδ T cells and Th22 cells. Nevertheless, under some certain conditions, AhR may not produce IL-22, and AhR^-/- mice can develop severe skin inflammation associated with higher IL-22 and IL-17 expression. The Notch signaling also promotes IL-22 expression via AhR induction in Th17 cells (65). Additionally, prostaglandin E2 (PGE2) enhances IL-22 production from both T cells and ILC3 via binding EP4 and EP2 receptors and blocking IRF-4, as well as activating AhR and cAMP signaling (66, 67) ( Figure 3 ). In the lungs, certain viral or bacterial microorganisms can convert tryptophan (Trp) into derivatives that promote IL-22 secretion. Of importance, IL-22 production from γδ T cells is manipulated through AhR- and Try-dependent mechanism via CD69 (68). And CD69 regulates LAT-1 expression, which determines the intracellular quantity of AhR and the uptake of Trp ( Figure 3 ). Moreover, both CARD^-/- and IDO^-/- mice can alter downstream Trp metabolites, for instance 3-IAID, with one depriving IL-22-promoting derivatives and the other favoring them, respectively (69). Taken together, these findings illustrate that controlling AhR signaling and Trp metabolites may be a powerful tool for regulating IL-22 functions.

During the early stage of influenza infection, studies has previously illustrated that IL22 is overexpressed by NK and NKT cells in the lung, resulting in the airway and parenchymal epithelium regeneration. Within two days after viral infection, IL-22 gene transcription in Tγδ, Tαβ and innate lymphoid cells is also increased in lung ( Table 2 ). However, IL22BP gene transcription is decreased. During the sublethal stage of viral infection, IL-22 can inhibit lung inflammation, reduce secondary infection and preserve the integrity of lung epithelium (70). Whereas IL-22^-/- mice infected with viral shows enhanced collagen accumulation and a defect in epithelial regeneration (70). Moreover, IL-22 can also prevent pulmonary fibrosis in a Bacillus subtilis induced model. Administration of IL-22 alleviates lung fibrosis, while inhibition of IL-22 leads to increased collagen accumulation in the lungs (71). In pneumococcal pneumonia, IL-22 gene is found to increase in the lung together with other cytokines, for example TNFα, IL-6, and IL-1. The absence of IL-22 makes the host vulnerable to pneumococcal infection, which indicates that the presence of IL22 is very important to control pneumococcal infection (72). IL-22 also plays a key role in host resistance to many other lung pathogens. During Klebsiella pneumonia infection, NK cells activation results in IL-22 production to protect lung tissue, and during infection with Streptococcus pneumoniae, TLR5 and DC cells activation leads to a repaid accumulation of ILC3s in the lungs to express IL-22 and defense against bacterial infection (73–75). During Chlamydia muridarum infection, IL-22 levels are rapidly increased in the lungs. Neutralization of IL-22 with anti-IL-22 mAbs can lead to impaired Th17 responses and deterioration of disease. Intranasal injection of IL-22 can significantly enhance Th17 response and have a protective effect following Chlamydia pneumoniae infection (76). After Aspergillus fumigatus pulmonary infection, the fungal burden is increased in IL-22^-/- mice, suggesting the critical role of IL-22 in the elimination of this pathogen (77). Additionally, IL-22 can also play a protective role in the barotrauma model, thereby reducing pulmonary edema and disintegration (78).

In the animal model of bleomycin induced lung injury, it is demonstrated that IL-22 and IL-17 are predominantly produced by Th17 cells. Inhibiting IL-22 during bleomycin injection can improve airway inflammation, indicating IL-22 has a proinflammatory effect; nevertheless, airway inflammation is also significantly reduced in IL-17^-/- mice with still high levels of IL-22 produced by T cells, suggesting IL-22 has a protective function for pulmonary fibrosis in deficiency of IL-17 (79, 80). Therefore, the proinflammatory effect of IL-22 may depend on the synergistic effect with IL-17 ( Table 2 ).

In peripheral blood of asthmatic patients and preclinical asthma models, serum IL-22 levels are increased. The recent studies have indicated IL-22 can induce the occurrence of asthma in preclinical models, but it can ameliorate inflammation during asthma exacerbation (81, 82). In ovalbumin induced asthma animal model, IL-22 neutralization with mAbs during sensitization stage of disease, which is similar to the pulmonary fibrosis research just mentioned above, evidently alleviated lung pathology and airway inflammation. Subcutaneous administration of IL-22 during sensitization leads to worse lung pathology and inflammation (83–85). Conversely, IL-22 neutralization after sensitization can result in increased lung inflammation, whereas IL-22 injection decreases chemokine expression, goblet cell hyperplasia, production of IL-25, eosinophil infiltration and constriction of the airway (82–85). The mechanism behind this dual effect in allergic airway inflammation is unclear, but it may involve inhibiting the production of IL-25 and CCL17 through airway epithelial repair, which may involve IL-10.

In conclusion, IL-22 is involved in a variety of lung diseases, making it a promising target for clinical development.

Although IL-22 does not appear to reduce virus titer during infections, studies have illustrated that IL-22 can reduce the pneumonia severity via the immune regulation and tissue protective or regenerative functions (86, 87). As COVID-19 is a respiratory disorder with similar pathological characteristics and symptoms to other serious pulmonary virus infections, it is reasonable to speculate that IL-22 may also serve to limit the severity of this disease. More importantly, recent studies have shown that IL-22 has potent immune boosting, antiviral, and antibacterial properties to respiratory syncytial virus, which could also extend to manage SARS-CoV-2 infection (88). Accordingly, compared with healthy control individuals, the IL-22⁺-Tc22 and IL-22⁺-Th22 numbers in adult-COVID-19 patients increased significantly, whether it is asymptomatic pneumonia, mild pneumonia, or severe pneumonia ( Figure 4 ). These findings further suggest that in the 0-12-year-old age group with asymptomatic disease course and uncomplicated adult cases, IL-22 expressed Tc22 cells are higher, which indicates that IL-22 has a protective effect (89). In contrast, the association between the increase of Tc17 cells and the severity of COVID-19 may reveal the destructive effect of co-expression of IL-17 and IL-22.

As the IL-22/IL-22R1 axis is involved in inflammation during virus infection, the expression patterns of IL-22/IL-22R1 on blood hematopoietic cells in SARS-CoV-2 infection have been well studied (90–93). The numbers of IL-22R1⁺ myeloid DC1, myeloid DC2, and plasmacytoid DC and the proportions of IL-22R1⁺ intermediate, non-classical, and classical monocytes higher in COVID-19 patients than controls at the presented day. Moreover, high proportions of mDC2 and IL-22R1⁺ non-classical monocytes show high HLA-DR expression and are therefore activated. Multivariate analysis is performed on all IL-22R1⁺ myeloid cells to distinguish the disease severity. However, correlation analysis between the concentration of plasma chemokines and IL-22R1⁺ cell subsets indicates that some subsets have protective effects, while others have pro-inflammatory effects (93, 94). Without stimulation, CD4⁺-T and NK lymphocytes produced IL-22. CD4⁺-T cells expressed IL-22R1, and its expression density defines two different functional subsets. The number of IL-22R1⁺ intermediate monocytes is negatively correlated with IFN-α, CRP and IL-6 in non-serious SARS-CoV-2 infection, whereas pDC and IL-22R1⁺ classical monocytes are positively correlated with pro-inflammatory chemokines IP-10 and MCP-1 in serious SARS-CoV-2 infections. Besides, researchers further demonstrate that IL-22 can reduce the expression of viral entry receptors, such as ACE2, TMPRSS2, and increase the expression of anti-viral proteins through IL-22/IL-22R1 pathway ( Figure 4 ) (95). Thus, these findings suggest that the IL-22/IL-22R1 signaling is involved in the pathological process of COVID-19, which can be protective during SARS-CoV-2 infections (93–95).

Recently, studies have demonstrated the roles of ILCs (innate lymphoid cells) in COVID-19 patients. Blood from severely infected COVID-19 patients were found that had fewer ILC precursor cells and ILCs than those mild cases. Of importance, in these severely infected COVID-19 patients, the expression of CD69 in ILCs was higher, which as a marker for tissue homing and activation. ILCs-CD69⁺ increased and blood ILCs decreased in severe infections, indicating that severely infected COVID-19 patients have more lung homing and activation (96). Further findings corroborate these results by confirming that higher ILCs abundance in blood was associated with shorter hospitalization. Additionally, the number of ILCs in the blood of hospitalized patients with SARS-CoV-2 infection decreased by 1.8 times (97). Collectively, these studies demonstrate that there are correlations between severe COVID-19 and decreased ILCs in the blood. As IL-22 plays critical functions in epithelial barrier integrity and ILCs are identified as the major source of IL-22 in response to lung pathogens stimulation (98), further studies are urgently needed to assess their exact roles in SARS-CoV-2 infection since current results regarding IL-22 and ILCs in COVID-19 individuals are obtained via analysis of blood periphery ( Figure 4 ).