Immune Evasion of Mycobacteria Via TREM2 Through Induction of Permissive Macrophages And Suppression Of Mincle/CARD9-Induced Anti-Mycobacterial Immunity

Abstract

Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, their mechanism of action remains unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages responded to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages responded to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhanced Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerated the elimination of mycobacterial infection, suggesting that TREM2/DAP12 signaling counteracts Mincle/FcRg/CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 to evade the host immunity.

Keywords: CARD9, C-type lectin receptors, TREM2, Macrophages, Mincle, Tuberculosis, Mycobacteria, Immune evasion, Innate Immunity, Macrophage, Mycolic acid, ITAM-coupled receptor