7 - Macrophages and Obesity Flashcards
What are macrophages and what do they do?
- Macrophages - dominant immune cells in adipose tissue
- Maintain adipocyte function, insulin sensitivity and glucose tolerance
Regular vs obese transgenic mice
Regular:
- Adipose tissue: ca.10–15% of Mφs positive for F4/80
- M2 phenotype
- Even Mφ tissue distribution
Obese:
- ca. 45–60% of F4/80+ Mφ
- M1 phenotype
- Mφ concentrated in ‘crown-like’ structures around dying adipocytes
- (F4/80: mouse monocyte/Mφ marker)
As obesity progresses, adipose tissue Mφ switch from M2-phenotype to M1
Crosstalk between innate and adaptive immune cells in adipose tissue
- CD4+ FOXP3+ Treg cells and alternatively activated macrophages, enriched in the visceral adipose tissue of lean mice, secrete IL-10 to enhance insulin action and glucose disposal in adipocytes.
-With over nutrition, engorged adipocytes undergo necrotic cell death, resulting in recruitment of classically activated macrophages to clear debris.
-In this context, adipose tissue macrophages expressing the prototypical molecules (MHC class II, CD1d, co-stimulatory molecules) and markers (CD11c) of antigen-presenting cells are potentially capable of presenting to T and B cells to promote adaptive immune responses.
-This is postulated to promote clonal expansion of CD4+ Th1 cells and increase infiltration by CD8+ T cells.
-In a feed forward loop, IFNγ production by CD4+ Th1 cells, and secretion of inflammatory cytokines and chemotactic factors by CD8+ T cells results in increased recruitment and classical activation of macrophages.
-Concomitant with this, numbers of immunosuppressive Treg cells decrease in adipose tissue with obesity, further contributing to the adipose tissue inflammation and insulin resistance.
-B cells, which infiltrate obese adipose tissue, can present antigens on MHC class I and II molecules to naïve T cells.
-IgG2c antibodies produced by mature B cells further amplifies adipose tissue inflammation and insulin resistance
Recruitment of monocytes, differentiation to M1
Secretion of anti-Inflammatory cytokines:
- IL-4, IL-10, IL-13, IL-33
Secretion of FFA (free fatty acids), SSA (saturated FA) Ox-LDL (oxidised low-density lipoprotein)
RBP4 (retinol- binding protein 4)
In turn, secretion of pro-inflammatory cytokines:
- TNF-α, IL-6, IL-1β, MCP-1, CCR2, CCR5
Lean state insulin sensitivity vs obese state insulin resistance
Insulin sensitivity:
- 4:1 M2:M1 ratio
- More eosinophils, T-reg cells
- Adiponectin enhances insulin sensitivity
Insulin resistance:
- More necrotic adipocytes
- Inverse correlation with T-reg cells
- More neutrophils
- Leptin resistance observed
- Low oxygen induces TLR4 expression
What drives beta-cell hyperplasia?
- Increased Mφ accumulation in islets primarily arises through local proliferation ofresident Mφ and their secretion of factors that drive beta-cell hyperplasia
Pancreatic hormone producing cells
- alpha cell
- alpha/beta cell
- beta cell
- delta cell
What major populations of macrophages can be detected in LEAN mice vs OBESE mice?
- In LEAN mice, two major populations of macrophages can be detected based on their anatomical distributions: peri-islet macrophages (pi-macs) (F4/80hi CD11c-) and intra-islet macrophages (ii-macs) (F4/80lo CD11chi). Both are islet-resident cells
- In contrast, in OBESITY, the size of islet is increased due to increased beta cell replication and cell size
Possible reasons for larger islets in obese mice?
- Stressed beta cells recruit more monocytes?
- Resident Mφ proliferate?
Interactions of pancreatic islet macrophage and pancreatic beta cells in obesity
- In obesity, elevated levels of glucose and free fatty acids can induce a pro-inflammatory phenotype of islet macrophages.
- As a result, macrophages produce increased amounts of proinflammatory cytokines such as IL-1β and TNF-α.
-These cytokines activate NF-κB and JNK pathways in beta cells and also exacerbate ER stress.
- Synergistically, these responses dampen beta cell GSIS. In addition to inflammatory cytokines, other mechanisms involving macrophage-mediated beta cell dysfunction exist.
- There mechanisms include: extracellular vesicles (EV) containing insulin released by beta cells and phagocytosed by islet macrophages; the formation of tunneling nanotubes (TNT) or gap junctions (GJ) between macrophages and beta cells allowing for bidirectional exchange of cellular contents.
- Obesity increases PDGF expression in islet macrophages via unclear mechanisms.
- Through PDGFR expressed in beta cells, PDGF promotes beta cell proliferation by activating downstream Erk signaling and inducing cell cycle gene (e.g., Ccnd1) expression.
Tunnelling nanotubes:
Generated by Mφ, allow transport of cytoplasmic material
between
What is the dominant immune cell type in adipose tissue?
Macrophages dominant immune cell type in adipose tissue
What differences are there in lean vs obese mice?
Comparisons between lean and obese mouse models show differences
in abundance, phenotype and localization of macrophages
What allows for formation of auto-Ab?
Communication between macrophages and B lymphocytes increases inflammation and allows formation of auto-Ab from B lymphocytes
What do pancreatic islets contain?
Pancreatic islets contain macrophages which interact with the insulin-producing beta-cells, driving their hyperplasia and dysfunction, characteristic of insulin-resistant state of type 2 diabetes
