OTULIN's role in immune tolerance and inflammation: pathways and therapeutic insights

The field of immunology has increasingly recognized ubiquitin-editing enzymes as pivotal regulators of immune balance, with OTULIN emerging as a central player in the maintenance of immune tolerance and the modulation of inflammatory processes. OTULIN, through its specialized deubiquitinase activity, acts at critical nodes of immune regulation, limiting inappropriate activation while enabling robust responses to genuine threats. Recent evidence highlights that OTULIN haploinsufficiency or dysfunction increases the risk of pathologic inflammation, especially in response to environmental and infectious stressors. Key studies have revealed OTULIN's influence over hematopoietic and stromal cells, particularly CD64+ monocytes and macrophages, and have unveiled connections to fundamental processes like NF-κB signaling, cytokine production, and immune cell crosstalk. Despite advances in characterizing its regulatory roles, significant gaps persist in our understanding of how OTULIN deficiency translates into varied disease phenotypes, the interplay with environmental triggers, and its therapeutic manipulation. Ongoing debates focus on the complexity of its regulatory network, the context-dependent nature of OTULIN's effects, and challenges in effectively targeting its pathway for clinical benefit.

This Research Topic aims to systematically dissect the molecular, cellular, and systemic actions of OTULIN in immune homeostasis, with an emphasis on its dual roles in restraining inflammation and preserving tolerance. The objective is to clarify the intracellular and extracellular mechanisms governing OTULIN's influence, ascertain how its dysfunction precipitates immune pathologies, and identify pathways that could be amenable to intervention. Key questions to be examined include: How does OTULIN orchestrate responses within immune and stromal cells? What signaling networks and transcriptional programs does it control? Which environmental or infectious exposures exacerbate OTULIN-related dysfunction? Ultimately, this Topic strives to propel research that bridges molecular understanding and therapeutic innovation, fostering new strategies for treating inflammatory and autoimmune diseases.

This Research Topic encompasses fundamental and translational research, focusing specifically on the regulatory spectrum of OTULIN in immune cells and tissues. Submissions should address the following areas or related themes:

-Molecular mechanisms of OTULIN-mediated ubiquitin editing in immune regulation
-OTULIN’s control of NF-κB, cytokine production, and other signaling pathways
-Crosstalk between OTULIN-expressing immune/stromal cells and their microenvironments
-The influence of environmental and infectious stimuli on OTULIN function and downstream effects
-Therapeutic strategies targeting OTULIN, including pharmacological modulators, gene editing, and immune reconstitution approaches

To advance a comprehensive understanding, we welcome original research articles, reviews, perspectives, and short communications. Innovative methodologies such as advanced imaging, single-cell or spatial multi-omic analyses, and computational modeling to elucidate OTULIN-regulated pathways are highly encouraged. Articles should emphasize mechanistic insight, translational potential, or both, advancing the field toward targeted therapies for inflammation and autoimmune disease.

Dr. Gewei Lian gains income from Beth Israel Deaconess Medical Center and Dr. Xiangming Ji is a full time associate professor at Penn State University. All other topic editors declare no conflict of interest