Cellular Innate Immunity: Macrophage

Question 1

Overview of macrophages

Answer 1

Question 2

Origins of macrophages

Answer 2

Macrophages originate from the embryonic and hematopoietic system

Question 3

The embryonic development of macrophage

Answer 3

Question 4

Functions of tissue resident macrophages

Answer 4

Macrophages with different origin can adopt different physiology and pathology roles

Question 5

The hematopoietic development of macrophage

Answer 5

Question 6

Common Macrophages Functions

Phagocytosis

Answer 6

• 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.

Question 7

Common Macrophages Functions

Cytotoxicity

Answer 7

Direct killing the release of cytotoxicity molecule
* TNF-alpha, Granzymes, NO, ROS
Direct killing through the antibody-dependent cellular cytotoxicity
* CD16 Fc Receptor.

Question 8

Common Macrophages Functions

Antigen Presentation

Answer 8

Express major histocompatibility complex (MHC) class II
Express co-stimulation molecule
* CD80, CD86, CD40

Question 9

Common Macrophages Functions

Cytokine Production

Answer 9

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

Question 10

Common Macrophages Functions

Wound Healing and Tissue Remodeling

Answer 10

• 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.

Question 11

M1 and M2 polarization of macrophages

Answer 11

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.

Question 12

Signal transduction pathways to M1 and M2 macrophage polarization

Answer 12

Question 13

Differential Macrophage Activation

Answer 13

Question 14

The inflammatory process of macrophages in infection

Answer 14

1. Recognize pathogen via PAMP
2. Recruitment and activation
3. Promote inflammatory response for clear pathogen
4. Resolve inflammatory and repair tissue

Question 15

Therapeutic perspective

Answer 15

Question 16

The Role of Macrophages in Cancer

Answer 16

• 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.

Question 17

Macrophages in the Cancer Initiation

Answer 17

• 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.

Question 18

Macrophages in the Established Tumor

Answer 18

Question 19

Macrophages as Therapeutic Targets

Answer 19

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