Depending on the inflammatory milieu, injury can result either in a tissue's complete regeneration or in its degeneration and fibrosis, the latter of which could potentially lead to permanent organ failure. Yet how inflammatory cells regulate matrix-producing cells involved in the reparative process is unknown. Here we show that in acutely damaged skeletal muscle, sequential interactions between multipotent mesenchymal progenitors and infiltrating inflammatory cells determine the outcome of the reparative process. We found that infiltrating inflammatory macrophages, through their expression of tumor necrosis factor (TNF), directly induce apoptosis of fibro/adipogenic progenitors (FAPs). In states of chronic damage, however, such as those in mdx mice, macrophages express high levels of transforming growth factor β1 (TGF-β1), which prevents the apoptosis of FAPs and induces their differentiation into matrix-producing cells. Treatment with nilotinib, a kinase inhibitor with proposed anti-fibrotic activity, can block the effect of TGF-β1 and reduce muscle fibrosis in mdx mice. Our findings reveal an unexpected anti-fibrotic role of TNF and suggest that disruption of the precisely timed progression from a TNF-rich to a TGF-β-rich environment favors fibrotic degeneration of the muscle during chronic injury.

Kidney injury is characterized by persisting inflammation and fibrosis, yet mechanisms by which inflammatory signals drive fibrogenesis remain poorly defined. RNA sequencing of fibrotic kidneys from patients with CKD identified a metabolic gene signature comprising loss of mitochondrial and oxidative phosphorylation gene expression with a concomitant increase in regulators and enzymes of glycolysis under the control of PGC1 and MYC transcription factors, respectively. We modeled this metabolic switch , in experimental murine models of kidney injury, and in human kidney stromal cells (SCs) and human kidney organoids. In mice, MYC and the target genes thereof became activated in resident SCs early after kidney injury, suggesting that acute innate immune signals regulate this transcriptional switch. , stimulation of purified human kidney SCs and human kidney organoids with IL-1 recapitulated the molecular events observed , inducing functional metabolic derangement characterized by increased MYC-dependent glycolysis, the latter proving necessary to drive proliferation and matrix production. MYC interacted directly with sequestosome 1/p62, which is involved in proteasomal degradation, and modulation of p62 expression caused inverse effects on MYC expression. IL-1 stimulated autophagy flux, causing degradation of p62 and accumulation of MYC. Inhibition of the IL-1R signal transducer kinase IRAK4 or inhibition of MYC as well as in human kidney organoids abrogated fibrosis and reduced tubular injury. Our findings define a connection between IL-1 and metabolic switch in fibrosis initiation and progression and highlight IL-1 and MYC as potential therapeutic targets in tubulointerstitial diseases.

Acute skeletal muscle injury triggers an expansion of fibro/adipogenic progenitors (FAPs) and a transient stage of fibrogenesis characterized by extracellular matrix deposition. While the perpetuation of such phase can lead to permanent tissue scarring, the consequences of its suppression remain to be studied. Using a model of acute muscle damage we were able to determine that pharmacological inhibition of FAP expansion by Nilotinib, a tyrosine kinase inhibitor with potent antifibrotic activity, exerts a detrimental effect on myogenesis during regeneration. We found that Nilotinib inhibits the damage-induced expansion of satellite cells in vivo, but it does not affect in vitro proliferation, suggesting a non cell-autonomous effect. Nilotinib impairs regenerative fibrogenesis by preventing the injury-triggered expansion and differentiation of resident CD45(-):CD31(-):α7integrin(-):Sca1(+) mesenchymal FAPs. Our data support the notion that the expansion of FAPs and transient fibrogenesis observed during regeneration play an important trophic role toward tissue-specific stem cells.

Pathologies characterized by lipomatous infiltration of craniofacial structures as well as certain forms of lipodystrophies suggest the existence of a distinct adipogenic program in the cephalic region of mammals. Using lineage tracing, we studied the origin of craniofacial adipocytes that accumulate both in cranial fat depots and during ectopic lipomatous infiltration of craniofacial muscles. We found that unlike their counterparts in limb muscle, a significant percentage of cranial adipocytes is derived from the neural crest (NC). In addition, we identified a population of NC-derived Lin 2 /a7 2 /CD34 1 /Sca-1 1 fibro/adipogenic progenitors (NC-FAPs) that resides exclusively in the mesenchyme of cephalic fat and muscle. Comparative analysis of the adipogenic potential, impact on metabolism, and contribution to the regenerative response of NC-FAPs and mesoderm-derived FAPs (M-FAPs) suggests that these cells are functionally indistinguishable. While both NC-and M-FAPs express mesenchymal markers and promyogenic cytokines upon damage-induced activation, NC-FAPs additionally express components of the NC developmental program. Furthermore, we show that craniofacial FAP composition changes with age, with young mice containing FAPs that are almost exclusively of NC origin, while NC-FAPs are progressively replaced by M-FAPs as mice age. Based on these results, we propose that in the adult, ontogenetically distinct FAPs form a diffused system reminiscent of the endothelium, which can originate from multiple developmental intermediates to seed all anatomical locations.

The suprachiasmatic nucleus plays a key role in the circadian secretion of adrenocortical hormones. However, there is evidence from mouse studies that components of the circadian clock are also expressed within the adrenal gland itself. In the present study we performed genome-wide expression profiling to determine whether the adrenal gland of rhesus monkeys shows temporal gene expression across a 24-h period. We identified 322 transcripts with rhythmic patterns of expression and found that the phase distribution of cycling transcripts varied across the day, with more genes showing activation during the night. We classified the transcripts by their function and clustered them according to their participation in common biochemical pathways: 1) catecholamine synthesis and reuptake; 2) cholesterol cleavage and dehydroepiandrosterone sulfate synthesis; 3) protein synthesis and turnover; and 4) the circadian clock mechanism. In an additional experiment, we assessed the expression of various clock genes at two time points, 12 h apart. We found that expression of Bmal1 and Cry1 was higher at 1300 h, or zeitgeber time 6, whereas expression of Per1 was higher at 0100 h (zeitgeber time 18). Expression levels of Rev-erbalpha were higher at 0100 h than at 1300 h (P<0.05), and immunohistochemistry revealed a strong expression of this transcription factor specifically in chromaffin cells of the adrenal medulla. Taken together, the data indicate that the primate adrenal gland shows rhythmic expression of genes associated with cell biology and synthesis of steroids and catecholamines. Moreover, they strongly imply the existence of an intrinsic circadian clock.