Chronic inflammation occurs when tissue injury and repair attempts overlap.

• It is characterized by infiltration of mononuclear cells, particularly macrophages and lymphocytes, which interact dynamically over the course of inflammation (recall that acute inflammation is characterized by neutrophil infiltration).
• As a result of infectious agents and/or prolonged inflammatory response, tissue damage occurs.
• Tissue repair attempts comprise angiogenesis (formation of blood vessels, which ultimately regress) and fibrosis, aka, scarring.
• Because macrophages constitute the primary leukocyte in chronic inflammation, we’ll focus on their origins and activation; however, be aware that other leukocytes, including neutrophils, can be found at sites of chronic inflammation.

MACROPHAGE ORIGINS & ACTIVATION

• Macrophages arise from hematopoietic cells that reside in the bone marrow of adults (in the fetus, hematopoietic cells reside in the yolk sac and liver).
  — These cells give rise to various blood cell lines, including the monocytes, which circulate in the vasculature.
• Outside of the circulation, monocytes differentiate to become macrophages, and reside scattered throughout the connective tissues of the body.
  – Additionally, tissue resident macrophages reside in the liver (Kupffer cells), spleen and lymph nodes (sinus histocytes), central nervous system (microglial cells) and in the alveoli of the lungs.
  – Collectively, we can refer to these macrophages as the mononuclear phagocyte system (formerly called the “reticuloendothelial system”; some authors even reject the notion of a “mononuclear phagocyte system”).
• Upon activation, macrophages engage in various activities:
  – Presentation of antigens to T lymphocytes.
  – Production of cytokines, which mediate inflammatory responses.
  – Production of growth factors and enzymes that promote tissue repair and inhibit inflammation.
• To accomplish these goals, macrophages have dynamic phenotypes reflective of their microenvironments.

Macrophage Activation

Be aware that some texts describe two distinct types of macrophage activation, classical and alternative, and the resulting macrophages as either Type 1 (aka, classical type) or Type 2 (aka, alternative type); however, research now suggests that these should not be thought of as dichotomous types, but, rather, as potential phenotypes that macrophages express in response to environmental stimuli.

Pro-inflammatory effects:

• Stimulation by specific cytokines, such as interferon gamma (aka, type II interferon) and/or by microbes activate macrophages to produce inducible nitric oxide, reactive oxygen species, and lysosomal enzymes, which are antimicrobial.
• These activated macrophages also produce inflammatory cytokines and chemokines:
  – Tumor necrosis factor and chemokines activate lymphocytes.
• Activated T lymphocytes produce interferon gamma, which, as we’ve indicated, triggers pro-inflammatory macrophage activation. Thus, T lymphocytes can act as part of a positive feedback loop with pro-inflammatory activated macrophages.

Anti-inflammatory effects:

• Anti-inflammatory stimuli include interleukins 13 and 4 (IL-13, IL-4).
  – In response to these stimuli, activated macrophages produce cytokines, such as interleukin-10 (IL-10), that inhibit inflammatory activity of T lymphocytes, natural killer cells, and macrophages; thus, interleukin 10 prevents excessive inflammation and damage to host cells.
  – These “alternatively activated” macrophages also produce growth factors that promote tissue repair, including vascular endothelial growth factor (VEGF), which facilitates angiogenesis, and transforming growth factor beta (TGF-ß), which facilitates deposition of extracellular matrix proteins for fibrosis.
• Interleukins 13 and 4 (IL-13 and IL-4) are produced by T lymphocytes; thus, T lymphocytes can also promote anti-inflammatory macrophage activation.

Fibrosis

Unfortunately, the pro-inflammatory feedback loop can be maladaptive when prolonged macrophage-lymphocyte interactions promote chronic inflammation, as seen in fibrosis of the lung.
– In the example, chronic inflammation led to the deposition of extracellular proteins at the cost of healthy lung alveolar tissues.

• Fibrosis is characterized by excessive collagen deposition in response to persistent stimulation; it results in tissue loss and organ failure.
  – Some common pathological conditions caused by organ fibrosis include liver cirrhosis, constrictive pericarditis, scleroderma, and lung fibrosis disorders.