Cellular Innate Immunity: Macrophage Flashcards
Overview of macrophages
Origins of macrophages
Macrophages originate from the embryonic and hematopoietic system
The embryonic development of macrophage
Functions of tissue resident macrophages
Macrophages with different origin can adopt different physiology and pathology roles
The hematopoietic development of macrophage
Common Macrophages Functions
Phagocytosis
- Macrophages are professional phagocytes and are highly specialized in removal of dying or dead cells, cellular debris, pathogen and toxins
- Pathogens killed by acidifying and digesting with lysosomal enzymes.
Common Macrophages Functions
Cytotoxicity
Direct killing the release of cytotoxicity molecule
* TNF-alpha, Granzymes, NO, ROS
Direct killing through the antibody-dependent cellular cytotoxicity
* CD16 Fc Receptor.
Common Macrophages Functions
Antigen Presentation
Express major histocompatibility complex (MHC) class II
Express co-stimulation molecule
* CD80, CD86, CD40
Common Macrophages Functions
Cytokine Production
Proinflammatory cytokines:
* IFN-gamma, IL-1B, IL-6, IL-12, IL-23, IL-27, TNF-alpha
Anti-inflammatory cytokines:
* Arg1, IDO, IL-10, TGF-Beta,
Chemokines:
* CXCL1 and CXCL2, CCL5 (RANTES), CXCL8, CXCL9, CXCL10 and CXCL11
Growth Factors:
* VEGF, VEGF-C, and -D, MMP9, PDGF, and TGF-Beta
Common Macrophages Functions
Wound Healing and Tissue Remodeling
- Macrophages produce proteases to remove damaged tissue.
- Macrophages produce factors that induce and speed angiogenesis.
- Macrophage secrete specific chemokines that recruit fibroblast, Th2 cells and regulatory T cells.
- Macrophage express immunoregulatory proteins to inhibit the inflammatory response.
M1 and M2 polarization of macrophages
Macrophages can polarize to pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes.
M1activation is associated with inflammation, tumor resistance, and graft rejection.
M2 activation is associated with immunoregulation, matrix deposition, remodeling, and graft rejection.
Signal transduction pathways to M1 and M2 macrophage polarization
Differential Macrophage Activation
The inflammatory process of macrophages in infection
- Recognize pathogen via PAMP
- Recruitment and activation
- Promote inflammatory response for clear pathogen
- Resolve inflammatory and repair tissue
Therapeutic perspective
The Role of Macrophages in Cancer
- Tumor-associated macrophage (TAM) are amongst the most abundant immune cells in tumors.
- Majority of TAM exert several tumor-promoting functions, including stimulation of angiogenesis, metastasis, and suppression of antitumor immunity.
- M2-like TAM have been shown to affect the efficacy of anticancer treatments contribute to therapy resistance.
Macrophages in the Cancer Initiation
- Macrophages (TAM) are play an important role in generation of a persistent inflammatory responses during tumor initiation.
- Macrophage involve in cancer-initiating inflammatory responses through their production of molecules such IL-6, TNF-alpha, and IFN-gamma.
- Macrophages also produce growth factors and cytokines that stimulate growth of epithelial cells that have spontaneoulsy acquired cancer-associated mutations.
Macrophages in the Established Tumor
Macrophages as Therapeutic Targets
Targeting TAM recruitment and survival
Depleting macrophage by CCL2 or CCR2 blockade can improve the efficacy of chemotherapy, radition therapy and immunotherapy.
Several CCR2 blockade combination clinical trials are therefore ongoing.
Targeting TAM cytotoxicity
Breast and ovarian tumor express high level of CD24
CD24 to interact with Siglec-10 on TAMs to inhibit phagocytosis.
Targeting TAM reprograming
The plasticity of macrophage allow repolarize TAM from M2 toward a pro-inflammatory M1 phenotype
