Editorial: Targeting signalling pathways in inflammatory diseases

COPYRIGHT © 2023 Baig, Thurston, Sharma, Atre, Saqib, Khabiya, Bharti and Poh. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 01 August 2023 DOI 10.3389/fimmu.2023.1241440

cysteine residues in MAL's TIR domain attenuates the inflammatory response, which may be due to MAL interactions with downstream inflammatory signaling molecules (9).
Upon TLR4 activation, the inflammatory response involves the activation of transcription factors such as NF-kB and AP1, thereby generating pro-inflammatory cytokines. Baig et al. reported the formation of a heterotrimeric complex of p38MAPK, PKCd, and MAL in LPS-stimulated macrophages (10). This reiterates the potential role of MAL in regulating inflammatory pathways via various protein interactions (10,11). On the basis that the MAL-PKCd interaction is crucial in inflammatory signaling mediated by TLR2/4 (10) and that PKCd phosphorylates the MAL TIR domain, Rajpoot et al. conducted a virtual screen of FDA-approved drugs that would disrupt the MAL-PKCd interaction (12). This screen revealed dorzolamide (DZD) as a novel therapeutic, where it suppressed the PKCd-MAL-p38 MAPK signaling axis to inhibit inflammation (12). A significant (42%) increment in survival was observed in DZD-treated mice as compared to LPS alone-injected mice, validating the abrogation of inflammatory response in drugtreated mice (12). MAL also interacts with c-Jun, a subunit of the AP-1 transcription factor complex that is activated upon LPS stimulation of TLR4 (13). The interaction of MAL with c-Jun resulted in the transactivation and translocation of c-Jun, which ultimately resulted in the production of proinflammatory cytokines (13), thus making the interaction between these two proteins a potential therapeutic target. Indeed, Mansi et al. proposed a repurposed anti-inflammatory drug Gefitinib that abrogated the interaction of MAL with c-Jun, thereby inhibiting the cell's inflammatory response (13).
As post-translational modifications seem to be the major contributing factor toward MAL's variable interactions and eventual inflammatory responses, we were interested to know all the potential phosphorylation and nitrosylation sites on the TIR domain ( Figure 1B). Modifications at these sites may variably impact the interactions with known and unknown interaction partners, regulators, and downstream mediators. Likely, MAL's interactions with kinases and other proteins vary temporally and spatially. Inadvertently, each of these interactions [ Figure 1A and reviewed in detail by Rajpoot et al. (5)] represent potential points of therapeutic intervention. Thus, it remains crucial to understand how MAL is regulated and what interactions it forms under the influence of different stimulants acting on different TLRs. Once defined, the impact of individual interactions can then be determined during disease progression. Based on the studies published so far, we hypothesize ( Figures 1C, D) that different MAL-mediated protein-protein interactions define the severity of chronic inflammation. In conclusion, unraveling the proteinprotein interactions of MAL would not only lead us to a greater understanding of the underlying signaling mechanisms that occur in the progression of various life-threatening chronic inflammatory conditions, but would also direct us toward the development of important therapeutic strategies for disease treatment.

Author contributions
Conceptualization and supervision: MSB; writing and editing: MB, TT, RS, RA, US, RK, SB, and CP. All authors contributed and approved the submitted version.

Funding
This work was supported by the Cumulative Professional Development Allowance (CPDA) and the Research Development Fund (RDF) from the Indian Institute of Technology Indore (IITI) to MSB.