Turning Off Inflammation: A Novel Anti-Inflammatory Switch in Macrophages

24 June 2014 by Jalees Rehman, posted in immunology, inflammation, macrophages

[Note: This is a guest post by Tauseef (@CellSpell), an excellent immunologist and one of my faculty colleagues at the University of Illinois, who is quite excited about science outreach and science blogging.]

Macrophages are important immune cells which regulate inflammation, host defense and also act as a 'clean-up crew'. They recognize, kill and engulf bacteria as well as cellular debris, which is generated during an acute infection or inflammation. As such, they are present in nearly all tissues of the body, engaging in 24/7 surveillance. Some macrophages in a tissue are derived from circulating blood monocytes which migrate into the tissue and become "phagocytic" - acquire to ability to "eat". Other macrophage types permanently reside within a tissue such as peritoneal macrophages in the abdomen or microglia in the brain. Macrophages constitute a highly diverse population of cells. For example, their tissue localization determines what genes are turned on in any given macrophage type and how they will function. One of the most important recent developments in macrophage biology and immunology has been the realization that tissue macrophages can be broadly divided into at least two very distinct subsets: M1 and M2.

 

Macrophage and Virus (via Shutterstock)

Macrophage and Virus (via Shutterstock)

Pro-inflammatory M1 macrophages are predominantly involved in digesting bacteria and debris. They release pro-inflammatory molecules which then attract other immune cells and inform them that their assistance in fighting off the infection is sorely needed. M2 macrophages, on the other hand, help resolve inflammation by secreting anti-inflammatory molecules and calming down their M1 cousins. During inflammation, both sets of macrophages are activated but M1 cells appear first and M2 later. This makes sense because it allows the body to first focus on fighting off the injury with its powerful M1 cells, but also prevents excessive damage by subsequently initiating an endogenous brake (M2 cells) to prevent excessive inflammation.

Inadequate activation of M2 cells during infection or inflammation can have disastrous effects. If the pro-inflammatory M1 cells have no anti-inflammatory counterpart, then they will keep on releasing pro-inflammatory molecules. These, in turn, will attract increasing numbers of immune cells and set in motion a vicious cycle of severe inflammation and massive fluid accumulation. If the levels of M1 activity are extremely high, some tissues such as the lung can be flooded with fluid and cells which prevent oxygen supply to the body, and ultimately result in death. Lower levels of persistent M1 cell activity may not lead to death, but could cause a simmering chronic inflammation and autoimmune diseases.

Restoring the balance of M1 and M2 cells, or selectively increasing M2 cells is becoming a hot area in immunology. If it were possible to increase M2 cells by turning on specific molecules or pathways, one could treat autoimmune diseases or prevent exaggerated inflammatory responses. This would be a far more elegant than relying on more conventional immune suppressants such as steroids which could compromise the body's ability to resist future infections.

A recent paper published in the journal Cell (2014) by Yasutaka Okabe and Ruslan Medzhitov, has identified a transcription factor which is specific for anti-inflammatory macrophages. The researchers used a gene array to screen for over 40,000 genes and found that the transcription factor GATA6 was a key regulator of whether peritoneal (abdominal) macrophages were pro-inflammatory or anti-inflammatory. More importantly, the researchers found that retinoic acid, an active metabolite of Vitamin A, increases the GATA6 levels in macrophages, and thus pushes them towards an anti-inflammatory identity. Genetic deletion of GATA6 or depletion of Vitamin A in the diet of mice resulted in peritoneal macrophages becoming more pro-inflammatory (M1-like).

Although the present study provides an evidence of the role of Vitamin A and its metabolite retinoic acid in the suppression of inflammation by activation of GATA6 in macrophages, some unanswered questions need to be addressed in future studies. The researchers showed that Vitamin A depletion pushes macrophages towards the pro-inflammatory M1-like identity, but the researchers did not try the converse: They did not test whether giving vitamin A to animals would increase anti-inflammatory macrophages. The researchers also did not track the individual macrophages to truly prove that the pro-inflammatory cells were actually converting into anti-inflammatory macrophages versus merely recruiting a pool of anti-inflammatory cells from the blood.

An important lesson that we can take away from this paper is that vitamins and their metabolites are regulators of the immune response. Either too little or too much Vitamin A may be detrimental because its metabolite retinoic acid could upset the finely regulated balance of the immune system. This study is one of the first to unravel the molecular switches which regulate the formation of pro-inflammatory and anti-inflammatory macrophages. We are only at the beginning of this exciting area of research and hopefully, in the years to come, selective manipulation of these switches will allow us to treat acute inflammatory and chronic autoimmune diseases for which few therapies are available.

 

- M. Tauseef (@CellSpell)

 

ResearchBlogging.org

Okabe Y, & Medzhitov R (2014). Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell, 157 (4), 832-44 PMID: 24792964

 


6 Responses to “Turning Off Inflammation: A Novel Anti-Inflammatory Switch in Macrophages”

  1. Madeeha Reply | Permalink

    An interesting study on how vitamins affect the "policeman" cells - macrophages and regulate our immunity. Nicely written Tauseef.

  2. Rizwan Siddiqui Reply | Permalink

    Excellent analysis of the article...well composite blog

  3. C Kirk Osterland Reply | Permalink

    Some dermal macrophages may be of interest as the M2 variety.Human tattooing has long been popular.It is my understanding that the tattoo pigments are taken up by macrophages.There they persist,not causing inflammation and not being cleared away.Tattoo's last a lifetime;thus I surmise that the pigment ingesting macrophages also have lifelong spans.

  4. Suhail Akhtar Reply | Permalink

    An exceptional post by Tauseef written in a simple yet interesting manner.

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