Novel Role for Btk in the Induction of Classically Activated M1 Macrophages (65.9)

Abstract

Abstract This study defines a critical role for Btk in regulating TLR-mediated APC activation and differentiation. Using Btk-deficient mice we examined the effects of LPS in regulating macrophage activity and function. Reduced levels of pro-inflammatory cytokines IL-12, IL-18 and IFN-γ were observed in Btk-deficient mice and ex vivo generated macrophages and dendritic cells (DCs) following acute LPS administration, whilst enhanced production of the anti-inflammatory cytokine IL-10 was observed. In response to diverse stimuli specific populations of macrophages are induced such that macrophage activation can be either pro-inflammatory or anti-inflammatory. Exposure to bacteria and IFN-γ results in the generation of classically activated (M1) macrophages which are microbicidal and secrete pro-inflammatory cytokines, whereas IL-10 is a key cytokine produced by alternatively activated immunomodulatory (M2) macrophages. Given the immunosuppressive environment observed in the absence of Btk we investigated macrophage population induction following treatment of APCs with either polarizing cocktails or with TLR4. Comparison of gene induction profiles for WT or Btk-deficient APCs revealed an inability of Btk deficient macrophages to become M1 effector macrophages. The predominance of M2 macrophages when Btk is absent is of crucial importance when considering therapeutic inhibition of Btk for the treatment of cancer or autoimmunity given the role of M2 macrophages in driving these pathologies.