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Suppressor of cytokine signaling 3 (SOCS3) is a feedback inhibitor of interleukin (IL)-6 signaling in macrophages. In the absence of this molecule, macrophages become extremely prone to an IL-6-dependent expression of arginase-1 (Arg1) and nitric oxide synthase (NOS)2, the prototype markers for alternative or classical macrophage activation, respectively. Because both enzymes are antipodean macrophage effector molecules in  Mycobacterium tuberculosis  ( Mtb ) infection, we assessed the relevance of SOCS3 for macrophage activation during experimental tuberculosis using macrophage-specific SOCS3-deficient (LysM cre SOCS3 loxP/loxP ) mice. Aerosol infection of LysM cre SOCS3 loxP/loxP  mice resulted in remarkably higher bacterial loads in infected lungs and exacerbated pulmonary inflammation. This increased susceptibility to  Mtb  infection was accompanied by enhanced levels of both classical and alternative macrophage activation. However, high Arg1 expression preceded the increased induction of NOS2 and at early time points of infection mycobacteria were mostly found in cells positive for Arg1. This sequential activation of Arg1 and NOS2 expression in LysM cre SOCS3 loxP/loxP  mice appears to favor the initial replication of  Mtb  particularly in Arg1-positive cells. Neutralization of IL-6 in  Mtb -infected LysM cre SOCS3 loxP/loxP  mice reduced arginase activity and restored control of mycobacterial replication in LysM cre SOCS3 loxP/loxP  mice. Our data reveal an unexpected role of SOCS3 during experimental TB: macrophage SOCS3 restrains early expression of Arg1 and helps limit  Mtb  replication in resident lung macrophages, thereby limiting the growth of mycobacteria. Together, SOCS3 keeps IL-6-dependent divergent macrophage responses such as  Nos2  and  Arg1  expression under control and safeguard protective macrophage effector mechanisms.

frontiers in immunology

Suppressor of Cytokine Signaling 3 in Macrophages Prevents Exacerbated Interleukin-6-Dependent Arginase-1 Activity and Early Permissiveness to Experimental Tuberculosis