Microbially cleaved immunoglobulins are sensed by the innate immune receptor LILRA2

Abstract

Microbial proteases degrade a variety of host proteins(1-3). However, it has remained largely unknown why microorganisms have evolved to acquire such proteases and how the host responds to microbially degraded products. Here, we have found that immunoglobulins disrupted by microbial pathogens are specifically detected by leukocyte immunoglobulin-like receptor A2 (LILRA2), an orphan activating receptor expressed on human myeloid cells. Proteases from Mycoplasma hyorhinis, Legionella pneumophila, Streptococcus pneumonia and Candida albicans cleaved the N-terminus of immunoglobulins. Identification of the immunoglobulin-cleaving protease from L. pneumophila revealed that the protease is conserved across some bacteria including Vibrio spp. and Pseudomonas aeruginosa. These microbially cleaved immunoglobulins but not normal immunoglobulins stimulated human neutrophils via LILRA2. In addition, stimulation of primary monocytes via LILRA2 inhibited the growth of L. pneumophila. When mice were infected with L. pneumophila, immunoglobulins were cleaved and recognized by LILRA2. More importantly, cleaved immunoglobulins were detected in patients with bacterial infections and stimulated LILRA2-expressing cells. Our findings demonstrate that LILRA2 is a type of innate immune receptor in the host immune system that detects immunoglobulin abnormalities caused by microbial pathogens.

Removal of a subset of non-essential genes fully attenuates a highly virulentMycoplasmastrain

“…In the present study, we suggest another mechanism that could contribute to activating the immune system. Indeed, Ig cleaved by several bacteria, including those generated by Mycoplasma hyorhinis , have been described as ligands of the innate immune receptor LILRA2 (28). Once bound to this receptor, it triggers the activation of the innate immune system.…”

Leukocyte Immunoglobulin-Like Receptors A2 and A6 are Expressed in Avian Macrophages and Modulate Cytokine Production by Activating Multiple Signaling Pathways

“…The LILRA genes, including LILRA1–6 , play an important role in the immune system of humans [ 1 , 7 ]. In chicken, some genes of the Ig superfamily such as TREM, CD300, SIRP, chicken Ig-like receptors (CHIR)-A, CHIR-B, CHIR-AB homologs and chicken leukocyte immunoglobulin receptor (LIR) were identified using bioinformatics approaches that may be important role in immune responses to high and low avian influenza virus [ 4 , 19 , 20 , 21 ].…”

“…The leukocyte immunoglobulin-like receptor (LILR) family consists of members that play inhibitory or activating roles on the genes of the proteins involved with the immune system and expressed in several primary innate immune cells (monocyte/macrophages, dendritic cells and CD4 + /CD8 + T cells) [ 1 , 2 , 3 ] and cell lines (HEK293 T cells, MDCK cells, HL-60 cells, thymoma BWZ.36 cells, epithelial cells and T cells) [ 1 , 4 , 5 , 6 ]. The LILR genes are highly homologous in the sequence of the extracellular regions and different in their sequences of the intracellular regions [ 7 , 8 ].…”

“…In humans, LILRA2 is a type of innate immune receptor in the host immune system that plays a role in the immune response to microbial pathogens such as Mycoplasma hyorhinis , Streptococcus pneumonia , Candida albicans and Legionella pneumophila [ 1 ] and conditions such as inflammatory bowel disease [ 17 ] and rheumatoid arthritis [ 18 ]. In addition, human LILRA6 is correlated with susceptibility to atopic dermatitis [ 13 ].…”

“…This suggests that LILRA2 and LILRA6 play a role in the modulation of immune responses but the fundamental mechanisms by which LILRA2 and LILRA6 regulate cytokine production are not well characterized in mammalian species. Currently, no data exist regarding the role of LILRA2 and LILRA6 in the activation of immune signaling pathways in mammalian and avian species, although it was recently discovered that LILRA2 and LILRA6 interact with SHP2 and LILRA6 binds with an MHC class I ligand but not with LILRA2 in dendritic cells (DC), suggesting that they could shape immune responses in monocytes [ 1 , 7 ].…”