The impact of impaired macrophage functions in cystic fibrosis disease progression

Abstract

The underlying cause of morbidity in cystic fibrosis (CF) is the decline in lung function, which results in part from chronic inflammation. Inflammation and infection occur early in infancy in CF and the role of innate immune defense in CF has been highlighted in the last years. Once thought simply to be consumers of bacteria, macrophages have emerged as highly sensitive immune cells that are located at the balance point between inflammation and resolution of this inflammation in CF pathophysiology. In order to assess the potential role of macrophage in CF, we review the evidence that: (1) CF macrophage has a dysregulated inflammatory phenotype; (2) CF macrophage presents altered phagocytosis capacity and bacterial killing; and (3) lipid disorders in CF macrophage affect its function. These alterations of macrophage weaken innate defense of CF patients and may be involved in CF disease progression and lung damage.

Inflammation in cystic fibrosis: An update

“…This study demonstrates that macrophage function in CF is abnormal and plays a central role in the inflammatory response. Recent studies also suggest that CF macrophages have difficulty switching classes, demonstrate a hyper‐inflammatory phenotype, have difficulty resolving inflammation, inadequately clear bacteria through phagocytosis, and have impaired efferocytosis . It is not clear if these impairments are due to dysfunctional CFTR, factors in the CF lung environment, or a combination of both.…”

“…Undifferentiated macrophages (M0) polarize into M1 macrophages when exposed to either IFN‐γ, GM‐CSF, or LPS. M1 macrophages express CD80 on their cell surfaces, secrete elevated amounts of reactive oxygen species and pro‐inflammatory mediators including TNF‐α, IL‐1β, IL‐6, IL‐12, IL‐23, IFN‐γ, CCL2, and RANTES, secrete little IL‐10, and possess antimicrobial and phagocytic activities . M0 macrophages are polarized into M2 macrophages when they are exposed to IL‐4, IL‐13, IL‐10, or M‐CSF.…”

“…In the acute inflammatory response, neutrophils are called into the site of infection during the first 3 days; next, M1 macrophages arrive a few days later; and then M2 macrophages appear 10 or more days after the initial infection to remove inflammatory stimuli through efferocytosis and resolve the inflammatory response. In CF, the normal acute inflammatory response appears to be impaired …”

“…Studies suggest CF macrophages have impaired ability to phagocytose bacteria. Monocytes from people with CF have low expression of CD11b, a receptor for opsonic phagocytosis of many bacteria including P aeurginosa . In addition, caveolin‐1 is decreased in activated CF macrophages and likely inhibits the macrophage's ability to internalize P aeruginosa .…”

“…M1 macrophages express CD80 on their cell surfaces, secrete elevated amounts of reactive oxygen species and pro-inflammatory mediators including TNF-α, IL-1β, IL-6, IL-12, IL-23, IFN-γ, CCL2, and RANTES, secrete little IL-10, and possess antimicrobial and phagocytic activities. [76][77][78] M0 macrophages are polarized into M2 macrophages when they are exposed to IL-4, IL-13, IL-10, or M-CSF. M2 macrophages express scavenger and mannose receptors, CD209, IL-1 receptor antagonist, IL-13Rα1, and arginase-1, secrete IL-4 and IL-13, inhibit polarization to M1 macrophages, and possess endocytotic functions.…”