Reparative inflammation takes charge of tissue regeneration

Abstract

Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies.

Disease tolerance and immunity in host protection against infection

“…When these responses fail per se to sustain the functional outputs of parenchyma tissues the default program becomes programmed cell death ( Figure 1). This is coupled to the induction of cellular and tissue regenerative responses that restore the functional output of damaged parenchyma tissues 3,23 . As discussed in further detail below, different types of infection impose distinct forms of stress and damage to host parenchyma cells, suggesting that tissue damage control mechanisms 3 might act in a somewhat pathogen class-specific manner that reflects these differences such as to effectively establish disease tolerance against diverse types of infection 6 .…”

“…Clearance of damaged and dying cells is associated with macrophage polarization towards the production of cytokines and pro-resolving lipid mediators 71 including IL-10 and 15-Deoxy-Δ-prostaglandin J 2 (15d-PGJ 2 ), respectively, which induce the expression HO-1 72,73 . This macrophage response is also associated with the production of growth factors, such as platelet-derived growth factor (PDGF) and cytokines, such as transforming growth factor-β1 (TGFβ1), which can act directly on parenchyma cells to promote tissue regeneration, orchestrating yet another layer of tissue damage control 23 .…”

“…The mechanism via which this occurs involves the repression Nrf2 81 , revealing a tight integration of stress and damage responses with subsequent tissue repair and regeneration programs restoring host homeostasis 23,80,82 (Figure 1, 2). How these apparently conflicting activities exerted by cytokines such as TNF or ROS are resolved remains to be understood 23 activation in macrophages 36 and T cells 92 exerts immunoregulatory effects that promote tissue damage control. Furthermore, HIF1α orchestrates a metabolic response in macrophages 40,93 and shifts the balance between T H 17 and T REG cells 94 , modulating immune-driven resistance and possibly disease tolerance to infection.…”

“…In this section we discuss how immune-driven resistance to a different pathogen classes regulates tissue damage control mechanisms to establish disease tolerance to those classes of pathogens. 6 and to involve the production of epidermal growth factors (EGF) and platelet derived growth factor (PDGF) family members as well as cytokines such as transforming growth factor (TGF)-β, which promote stem cell proliferation and/or differentiation into parenchyma cells and thereby restore tissue integrity and function 23 (Figure 4a). …”

Telomere attrition in beta and alpha cells with age

“…Our present data on lineage-specific telomere attrition dynamics support this. On the other hand, various stimuli can trigger tissue injury-activated multiple signal pathways; for example, hyperglycemia may trigger the reactive oxidative stress-cytokine-transcription factor system, or Wnt signaling system, in self-renewal adult stem cells (Karin and Clevers, 2016).…”