In response to stress, cells start transcriptional and transcription‐independent programs that can lead to adaptation or death. Here, we show that multiple inducers of autophagy, including nutrient depletion, trigger the activation of the IKK (IκB kinase) complex that is best known for its essential role in the activation of the transcription factor NF‐κB by stress. Constitutively active IKK subunits stimulated autophagy and transduced multiple signals that operate in starvation‐induced autophagy, including the phosphorylation of AMPK and JNK1. Genetic inhibition of the nuclear translocation of NF‐κB or ablation of the p65/RelA NF‐κB subunit failed to suppress IKK‐induced autophagy, indicating that IKK can promote the autophagic pathway in an NF‐κB‐independent manner. In murine and human cells, knockout and/or knockdown of IKK subunits (but not that of p65) prevented the induction of autophagy in response to multiple stimuli. Moreover, the knockout of IKK‐β suppressed the activation of autophagy by food deprivation or rapamycin injections in vivo , in mice. Altogether, these results indicate that IKK has a cardinal role in the stimulation of autophagy by physiological and pharmacological stimuli.

The class B scavenger receptor CD36 is a component of the pattern recognition receptors on monocytes that recognizes a variety of molecules. CD36 expression in monocytes depends on exposure to soluble mediators. We demonstrate here that CD36 expression is induced in human monocytes following exposure to IL‐13, a Th2 cytokine, via the peroxisome proliferator‐activated receptor (PPAR)γ pathway. Induction of CD36 protein was paralleled by an increase in CD36 mRNA. The PPARγ pathway was demonstrated using transfection of a PPARγ expression plasmid into the murine macrophage cell line RAW264.7, expressing very low levels of PPARγ, and in peritoneal macrophages from PPARγ‐conditional null mice. We also show that CD36 induction by IL‐13 via PPARγ is dependent on phospholipase A2 activation and that IL‐13 induces the production of endogenous 15‐deoxy‐Δ^12,14‐prostaglandin J₂, an endogenous PPARγ ligand, and its nuclear localization in human monocytes. Finally, we demonstrate that CD36 and PPARγ are involved in IL‐13‐mediated phagocytosis of Plasmodium falciparum‐parasitized erythrocytes. These results reveal a novel role for PPARγ in the alternative activation of monocytes by IL‐13, suggesting that endogenous PPARγ ligands, produced by phospholipase A2 activation, could contribute to the biochemical and cellular functions of CD36.

Colonic macrophages are considered to be major effectors of inflammatory bowel diseases (IBDs) and the control of gut inflammation through C-type lectin receptors is an emerging concept. We show that during colitis, the loss of dectin-1 on myeloid cells prevents intestinal inflammation, while the lack of mannose receptor (MR) exacerbates it. A marked increase in dectin-1 expression in dextran sulfate sodium (DSS)-exposed MR-deficient mice supports the critical contribution of dectin-1 to colitis outcome. Dectin-1 is crucial for Ly6ChighCCR2high monocyte population enrichment in the blood and their recruitment to inflamed colon as precursors of inflammatory macrophages. Dectin-1 also promotes inflammasome-dependent interleukin-1β (IL-1β) secretion through leukotriene B4 production. Interestingly, colonic inflammation is associated with a concomitant overexpression of dectin-1/CCL2/LTA4H and downregulation of MR on macrophages from IBD patients. Thus, MR and dectin-1 on macrophages are important mucosal inflammatory regulators that contribute to the intestinal inflammation.