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Toll-like receptors (TLR) are transmembrane pattern recognition receptors that recognize microbial ligands and signal for production of inflammatory cytokines and type I interferon in macrophages and dendritic cells (DC). Whereas TLR-induced inflammatory mediators are required for pathogen clearance, many are toxic to the host and can cause pathological inflammation when over-produced. This is demonstrated by the role of TLR-induced cytokines in autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Because of the potent effects of TLR-induced cytokines, we have diverse mechanisms to dampen TLR signaling. Here, we highlight three pathways that participate in inhibition of TLR responses in macrophages and DC, and their implications in autoimmunity; A20, encoded by the TNFAIP3 gene, Lyp encoded by the PTPN22 gene, and the BCAP/PI3K pathway. We present new findings that Lyp promotes TLR responses in primary human monocytes and that the autoimmunity risk Lyp620W variant is more effective at promoting TLR-induced interleukin-6 than the non-risk Lyp620R protein. This suggests that Lyp serves to downregulate a TLR inhibitory pathway in monocytes, and we propose that Lyp inhibits the TREM2/DAP12 inhibitory pathway. Overall, these pathways demonstrate distinct mechanisms of negative regulation of TLR responses, and all impact autoimmune disease pathogenesis and treatment., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.

Mycobacterium tuberculosis(Mtb) protein tyrosine phosphatase B (mPTPB) is a virulencefactor secretedby the pathogen and mediates mycobacterial survival in macrophagesby targeting host cell immune responses. Consequently, mPTPB representsan exciting new target to combat tuberculosis (TB) infection. We describea medicinal chemistry oriented approach that transforms a benzofuransalicylic acid scaffold into a highly potent (IC50= 38nM) and selective mPTPB inhibitor (>50 fold against a large panelof PTPs). Importantly, the inhibitor is capable of reversing the alteredhost immune responses induced by the bacterial phosphatase and restoringthe macrophage’s full capacity to secrete IL-6 and undergoapoptosis in response to interferon-γ stimulation, validatingthe concept that chemical inhibition of mPTPB may be therapeuticallyuseful for novel TB treatment. The study further demonstrates thatbicyclic salicylic acid pharmacophores can be used to deliver PTPinhibitors with high potency, selectivity, and cellular efficacy. [ABSTRACT FROM AUTHOR]