The Dual Role of Antimicrobial Peptides in Autoimmunity

Abstract

Autoimmune diseases (AiDs) are characterized by the destruction of host tissues by the host immune system. The etiology of AiDs is complex, with the implication of multiple genetic defects and various environmental factors (pathogens, antibiotic use, pollutants, stress, and diet). The interaction between these two compartments results in the rupture of tolerance against self-antigens and the unwanted activation of the immune system. Thanks to animal models, the immunopathology of many AiDs is well described, with the implication of both the innate and adaptive immune systems. This progress toward the understanding of AiDs led to several therapies tested in patients. However, the results from these clinical trials have not been satisfactory, from reversing the course of AiDs to preventing them. The need for a cure has prompted many investigators to explore alternative aspects in the immunopathology of these diseases. Among these new aspects, the role of antimicrobial host defense peptides (AMPs) is growing. Indeed, beyond their antimicrobial activity, AMPs are potent immunomodulatory molecules and consequently are implicated in the development of numerous AiDs. Importantly, according to the disease considered, AMPs appear to play a dual role in autoimmunity with either anti- or pro-inflammatory abilities. Here, we aimed to summarize the current knowledge about the role of AMPs in the development of AiDs and attempt to provide some hypotheses explaining their dual role. Definitely, a complete understanding of this aspect is mandatory before the design of AMP-based therapies against AiDs.

Keywords: antimicrobial host defense peptides; autoimmune diseases; cathelicidin; defensin; innate immunity.

FIGURE 1

Friend or foe: roles of antimicrobial peptides (AMPs) in autoimmune diseases. AMPs have a dysregulated expression in many tissues affected by autoimmune diseases, where they can promote or prevent the autoimmune response. On one side, as shown in psoriasis, systemic lupus erythematosus (SLE), and type 1 diabetes (T1D), cathelicidin (Cath) produced by neutrophils (N) forms immune complexes with self-nucleic acids, activating conventional and plasmacytoid dendritic cells (cDCs and pDCs, respectively) to release inflammatory cytokines which boost the autoimmune response. Besides, in psoriasis and in rheumatoid arthritis, posttranslational modifications of AMPs can generate neo-self-antigens recognized by effector T cells (Th1/Th17) and produce autoantibodies (AutoAbs). Moreover, in rheumatoid arthritis, AMPs directly support cartilage destruction by acting on osteoblasts and osteoclasts. On the other side, AMPs can also prevent autoimmune diseases, as shown in T1D. The gut microbiota-derived metabolites short-chain fatty acids (SCFAs) can induce AMP expression in pancreatic islets, and these AMPs directly or indirectly induce protective and regulatory immune cells including macrophages (Mregs), B cells (Bregs), and T cells (Tregs). In multiple sclerosis, mBD14 and Fasciola hepatica helminth defense molecule 1 (FhHDM1) show similar immunoregulatory functions and protective effects in a mouse model of the disease. h, human; m, mouse, BD, beta-defensin; HNP, alpha-defensin; SjS, Sjögren syndrome.