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As main drivers of leukocyte recruitment during inflammatory reactions, chemokines act as mediatrs of alarmins in priming host defense responses after tissue exposure to toxic or infectious agents, immunomediated damage, and in inflammation-driven tumors. Chemokines can therefore be considered alarm signals generated by tissues in a broad number of conditions, and mechanisms controlling chemokines biological activities are therefore key to regulate tissue reactions induced by alarmins. By transporting, presenting or scavenging different sets of chemokines, atypical chemokine receptors represent an emerign subfamily of chemokine receptors which operates in tissues as chemokine gatekeepers in order to establish and shape their gradients and coordinate leukocyte recruitment.

The early events linking diet-induced adipose tissue inflammation and insulin resistance remain poorly understood. In this issue of Cell Metabolism, Kawano et al. (2016) show that infiltration of colonic pro-inflammatory macrophages orchestrated by the intestinal CCL2/CCR2 axis kick-starts this process during high-fat-diet feeding.

Chemokines coordinate leukocyte recruitment during inflammatory and immune responses through the interaction with a distinct subfamily of G protein-coupled receptors. The magnitude of the cellular response elicited by chemokines is dictated by the level of receptor expression at the plasma membrane, which is the balance of finely tuned endocytic and recycling pathways. Recent data have revealed that receptor trafficking properties can drive chemokine receptors to lysosomal degradation or recycling pathways, producing opposite effects on the strength of the intracellular signaling cascade. This review will cover recent advances on the molecular mechanisms underlying chemokine receptor internalization, recycling and degradation pathways, with particular attention to structural motifs present in receptor intracellular domains and their interacting adaptor proteins that modulate receptor trafficking and dictate proper biological response.

Chemokines are a key component of cancer-related inflammation. Chemokines and chemokine receptors are downstream of genetic events that cause neoplastic transformation and are components of chronic inflammatory conditions, which predispose to cancer. Components of the chemokine system affect in a cell autonomous or non-autonomous way multiple pathways of tumor progression, including: leukocyte recruitment and function; cellular senescence; tumor cell proliferation and survival; invasion and metastasis. Available information in preclinical and clinical settings suggests that the chemokine system represents a valuable target for the development of innovative therapeutic strategies.

Tumor-associated macrophages (TAMs) can influence cancer progression and metastasis, but the mechanism remains unclear. Here, we show that breast TAMs abundantly produce CCL18, and its expression in blood or cancer stroma is associated with metastasis and reduced patient survival. CCL18 released by breast TAMs promotes the invasiveness of cancer cells by triggering integrin clustering and enhancing their adherence to extracellular matrix. Furthermore, we identify PITPNM3 as a functional receptor for CCL18 that mediates CCL18 effect and activates intracellular calcium signaling. CCL18 promotes the invasion and metastasis of breast cancer xenografts, whereas suppressing PITPNM3 abrogates these effects. These findings indicate that CCL18 derived from TAMs plays a critical role in promoting breast cancer metastasis via its receptor, PITPNM3.

Introduction Chemokine receptors include a set of molecules referred to as “atypical” chemokine receptors (ACR) because unable to induce directional cell migration and elicit conventional GPCR signalling. As no signaling activity has been observed after ACR engagement by their ligands, they are presently considered “silent” receptors. D6 is an ACR with scavenger activity on inflammatory CC chemokines with a non-redundant role for appropriate regulation of innate immunity and inflammation. Methods D6 expression was evaluated by FACS and confocal microscopy. Chemokine degradation was measured by ELISA test. Protein phosphorylation levels were detected by western blot. Results Our previous data showed that, differently from CCR5, ligand induces D6 up-regulation on plasma membrane through a rapid mobilization of receptor from recycling endosomes, thus improving its scavenging performance. Here we report that in cells expressing D6 or CCR5, ligand engagement causes a massive actin cytoskeleton reorganization and changes receptors colocalization with actin filaments in a completely opposite fashion. Both receptors signal to actin cytoskeleton by phosphorylating cofilinA through the Rac1-PAK1-LIMK1-dependent pathway. However, opposite to CCR5, D6 activates this pathway via a beta-arrestin-dependent, G protein-independent mechanism. Inhibition of each component of this signaling cascade completely abrogates D6 adaptive upregulation and scavenging activity. Conclusion D6, and possibly ACR in general, are signaling receptors exerting their regulatory functions on inflammation and immunity via the activation of a distinct signaling pathway.