Editors' ChoiceImmunology

New connections: Decoding macrophages in disease

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Science Signaling  21 May 2019:
Vol. 12, Issue 582, eaax6493
DOI: 10.1126/scisignal.aax6493

Deciphering how macrophages are reprogrammed in disease may lead to better patient therapies.

Chronic inflammation and metabolic stress are hallmarks of obesity and are linked to the development and progression of various diseases. Inflammation is associated with various cell-derived signals that alter gene expression in immune cells called macrophages that induce them to either encourage an immune response or promote tolerance to the condition. Two studies that uncover the distinct ways in which macrophages are reprogrammed in response to specific signals may reveal how to better prognose and treat patients. Cassetta et al. examined macrophage states in the context of cancer. Cancers are particularly adept at inducing a nonclassical, tolerant state in macrophages that infiltrate the tumor region, commonly called “tumor-associated macrophages” (TAMs). The authors analyzed immune cells from breast or endometrial cancer patients and healthy volunteers and identified components in the transcriptome of TAMs that were cancer type–specific and different from those of both tissue-resident macrophages and monocytes (the cell type from which macrophages are derived). These alterations included numerous genes encoding transmembrane receptors, soluble factors, transcription factors, immune regulatory receptors, proapoptotic molecules, and proangiogenic factors. Using cocultures, the authors discovered that the breast cancer TAM-specific transcriptome was shaped by the tumor-secreted cytokines colony-stimulating factor 1 and tumor necrosis factor-α and included the poor-survival prognostic gene expression markers SIGLEC1 and CCL8. In turn, production of those gene products (the cell adhesion protein SIGLEC1 and the cytokine CCL8) in TAMs promoted motility in tumor cells. This insight may improve efforts to therapeutically target TAMs in patients.

Inflammation and metabolic stress are associated with diseases other than cancer, notably critical illnesses, such as type 2 diabetes, chronic infection, and sepsis. Patients with burn injuries and chronic metabolic disorders, for example, have an increased abundance of free fatty acids and M2-polarized macrophages in the adipose tissue and the liver, which impairs wound healing and contributes to disease progression. In last week’s issue of Science Signaling, Fischer et al. showed how macrophages were reprogrammed differently in response to lipopolysaccharide (LPS), a “danger signal” associated with gram-negative bacterial infections, and the fatty acid palmitate, which is produced by adipose (fat) tissue. Using single-cell analysis methods, the authors showed that macrophages had a classical proinflammatory (“M1-polarized”) response to LPS but a suppressive, anti-inflammatory (“M2-polarized”) response to chronic palmitate exposure, each associated with specific transcriptional programs and signaling pathway activities. Given that palmitate is secreted from adipose layers around tumors, such as melanomas, where it facilitates tumor growth–promoting lipid metabolism and impairs therapeutic efficacy, one might extend these observations and suspect that the presence of palmitate may also be contributing directly to the reprogramming of TAMs. Together, these studies advance our knowledge of how immune cells are reprogrammed in response to diverse signals in their microenvironment. Understanding these mechanisms—particularly in the context of inflammation and obesity—may facilitate the development of not only better immunotherapies for patients but also better disease models that incorporate the multicellular microenvironment that is increasingly acknowledged to be a critical factor in disease progression and clinical outcome.

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