Neutrophils instruct homeostatic and pathological states in naive tissues

Abstract

Immune protection relies on the capacity of neutrophils to infiltrate challenged tissues. Naive tissues, in contrast, are believed to remain free of these cells and protected from their toxic cargo. Here, we show that neutrophils are endowed with the capacity to infiltrate multiple tissues in the steady-state, a process that follows tissue-specific dynamics. By focusing in two particular tissues, the intestine and the lungs, we find that neutrophils infiltrating the intestine are engulfed by resident macrophages, resulting in repression of Il23 transcription, reduced G-CSF in plasma, and reinforced activity of distant bone marrow niches. In contrast, diurnal accumulation of neutrophils within the pulmonary vasculature influenced circadian transcription in the lungs. Neutrophil-influenced transcripts in this organ were associated with carcinogenesis and migration. Consistently, we found that neutrophils dictated the diurnal patterns of lung invasion by melanoma cells. Homeostatic infiltration of tissues unveils a facet of neutrophil biology that supports organ function, but can also instigate pathological states.

Neutrophil Diversity in Health and Disease

“…Moreover, owing to their increased inflammatory activity, accumulated aged neutrophils have also been reported to promote vascular damage and disease; for instance, relative to controls, they contributed to increasing infarction size lesions and vaso-occlusion in mouse models of myocardial infarction and sickle cell disease, respectively [37,43]. Finally, as shown in multiple mouse studies, there is strong evidence that, in the absence of inflammatory insults, neutrophils are not necessarily confined to the BM, blood, and margination sites (mostly the lungs and spleen), but are able to transit into, and remain in, many tissues where they might exert organ-specific functions [44] (Figure 1). Perhaps consistent with specialized macrophages residing in the liver or brain (i.e., Kupffer cells or microglia) [45], it is reasonable to speculate that there may also be specialized resident neutrophils within other tissues or sites, although this remains to be investigated.…”

“…As observed in humans, based on differential surface marker expression, circulating mouse neutrophils exhibit heterogeneity that associates with distinct effector activities [5,37,[40][41][42][43]. In mice as in humans, neutrophils not only marginate in the spleen, liver, and lung vasculature but also transit and reside in other organs such as muscle, skin, lymph nodes, and intestine [44]. In the mouse spleen, three neutrophil subpopulations localized in the red pulp or MZ participate in emergency granulopoiesis (Ly6G int ) and pneumococcal clearance (Ly6G high ) [48], and can regulate antibody production in MZ B cells (NB H , as observed in humans) [47].…”

“…Perhaps consistent with specialized macrophages residing in the liver or brain (i.e., Kupffer cells or microglia) [45], it is reasonable to speculate that there may also be specialized resident neutrophils within other tissues or sites, although this remains to be investigated. Regarding function, intestinal CD169 + macrophagemediated neutrophil phagocytosis has been shown to reduce the production of interleukin (IL)-23 and lower the secretion of granulocyte colony-stimulating factor (G-CSF), thus distally controlling granulopoiesis within the BM [44]. In the lung, neutrophil infiltration could alter the circadian regulation of gene transcription as well as the susceptibility to develop metastasis in tumor mouse models [44].…”

“…Regarding function, intestinal CD169 + macrophagemediated neutrophil phagocytosis has been shown to reduce the production of interleukin (IL)-23 and lower the secretion of granulocyte colony-stimulating factor (G-CSF), thus distally controlling granulopoiesis within the BM [44]. In the lung, neutrophil infiltration could alter the circadian regulation of gene transcription as well as the susceptibility to develop metastasis in tumor mouse models [44]. Of note, mass cytometry analysis of multiple tissues has shown that, of all myeloid subsets, neutrophils display the highest degree of heterogeneity [46], supporting the concept that specialized neutrophils are present within different organs.…”

MASTers of neutrophil homeostasis

“…suggest that MCs promote neutrophil clearance in the bone marrow and spleen; however, given the high frequencies of MCs in mucosal linings, it is tempting to speculate that the observations could be generalized to other neutrophil‐retaining organs such as lungs or intestine, where IL‐17 production is most abundant. Indeed, these sites harbor pools of tissue neutrophils as shown by recent multiphoton imaging studies of parabiotic mice . In the colon, neutrophils resided in tissue parenchyma in close proximity to interstitial macrophages .…”